Patent Watch: In re Rosuvastatin Calcium Patent Litig.

by BakerHostetler

"The law does not require that no competent attorney or alert inventor could have avoided the error sought to be corrected by reissue."

On December 14, 2012, in In re Rosuvastatin Calcium Patent Litig., the U.S. Court of Appeals for the Federal Circuit (Newman,* Mayer, Plager) affirmed the district court's judgment that U.S. Reissue Patent No. 37,314 (a reissue of U.S. Patent No. 5,260,440), which related to rosuvastatin marketed by AstraZeneca as Crestor® for the control of cholesterol and the treatment of atherosclerosis, was not invalid, enforceable and infringed by Aurobindo Pharma Ltd., Mylan Pharmaceuticals Inc., Apotex Corp., Cobalt Pharmaceuticals Inc. and Cobalt Laboratories Inc., Sun Pharmaceutical Industries, Ltd., Teva Pharmaceuticals USA, Inc., Par Pharmaceuticals, Inc., and Sandoz, Inc. The Federal Circuit stated:

The Defendants challenge patent validity on the ground of obviousness. Obviousness is decided as a matter of law based on four basic factual inquiries . . . (1) the scope and content of the prior art, (2) the level of ordinary skill in the field of the invention, (3) the differences between the claimed subject matter and the prior art, and (4) any objective indicia of unobviousness, such as commercial success or long-felt need, or failure of others.

The Defendants identified as the closest prior art European Patent Office Publication No. 0 367 895 of the Sandoz company ("Sandoz"), published May 16, 1990, which describes numerous pyrimidine-based statin compounds, including a compound designated as Compound 1b [that the Defendants argued] would be a good "lead compound" for further research [and] the change of the -CH3 group to a -SO2CH3 group would have been obvious because it would make Compound 1b more hydrophilic. The Defendants stated that numerous publications taught that liver-selective statins may have fewer undesirable side effects, and that hydrophilic statins are more liver-selective. The Defendants argued that persons of ordinary skill in this field would have been motivated to make Sandoz Compound 1b more hydrophilic, and that the C2 position was the logical place to modify Compound 1b because the other parts of the structure were known to be essential to statin activity. The Defendants argued that a person of ordinary skill would have considered a limited number of common substitutions, including a sulfonyl "spacer" -SO2- at the C2 position to increase hydrophilicity. The Defendants argued that a person of ordinary skill would have predicted that this change would produce a statin with fewer adverse side effects, thereby rendering the compound obvious.

In response, the Plaintiffs pointed out that Sandoz Compound 1b demonstrated unexpected increased toxicity, and therefore was not an encouraging lead compound. The Plaintiffs stated that other compounds in the Sandoz European application, such as Compound 11, demonstrated better in vitro potency. The Plaintiffs responded to the argument that in 1991 a scientist would have known that Compound 1b should be made more hydrophilic, by pointing to publications that state that lipophilic substituents at the C2 position, the converse of hydrophilic, can increase statin potency. The Plaintiffs argued that the prior art provided no suggestion of rosuvastatin's unexpectedly superior properties as compared with Compound 1b or any other known compound, thus creating no "reasonable expectation of success."

The Plaintiffs highlighted the unpredictability that was associated with statin development. For example, the pyrrole-based statin corresponding in all other structural aspects to the pyrimidine-based rosuvastatin displayed toxic side effects. The Plaintiffs pointed out that at least five pharmaceutical companies had abandoned their research on statins with pyrimidine cores, on the prevailing belief that pyrimidine-based statins were not promising leads to improved products. The Plaintiffs pointed out that no reference, or combination of references, suggested that the previously unknown molecule rosuvastatin would have its advantageous properties. The Plaintiffs pointed to objective indicia of non-obviousness, including commercial success, long felt but unfilled need, failure of others, and unexpected results as support for the district court's judgment of unobviousness. . . .

The district court concluded that the Defendants did not demonstrate the required motivation for selecting Sandoz Compound 1b as a lead compound, or for making this specific sulfonyl change in the Compound 1b molecule. We agree that "obvious to try" was negated by the general skepticism concerning pyrimidine-based statins, the fact that other pharmaceutical companies had abandoned this general structure, and the evidence that the prior art taught a preference not for hydrophilic substituents but for lipophilic substituents at the C2 position. The district court correctly held that patent invalidity on the ground of obviousness had not been shown for the compound rosuvastatin. That ruling is affirmed. . . .

The Defendants also argued that the '314 patent was improperly reissued, arguing that the statutory reissue requirement of error without deceptive intent had not been met. . . . The Defendants argued that Shionogi deliberately presented a claim in the '440 patent that overlapped the products in the Sandoz reference in an attempt to get greater protection. The Defendants also argued that Shionogi acted deliberately in obtaining only generic claims in the '440 patent in order to conceal the rosuvastatin species. The Plaintiffs pointed out that rosuvastatin was specifically described in the specification as the most effective of the four compounds that are described with test data.

[F]or reissue purposes "error is established where there is no evidence that the appellant intentionally omitted or abandoned the claimed subject matter." Here, the district court found as fact that Shionogi erred by failing to file an IDS citing the Sandoz and Bayer references, and by omitting a specific claim to the preferred species. However, the court found no evidence of a deliberate choice to omit or abandon the rosuvastatin species, which was described in the specification as the most effective product. . . .

The district court received live testimony from the purported culprits, and found that "the evidence adduced in this case shows no such deliberate choices . . . and no violations of rules or statutes that would render the reissue of the '440 patent improper." In discussing the scope of the claims, the district court found that Ms. Kitamura credibly testified that she was unaware that there was overlap between the claims of the '440 application and the prior art because "the internal Shionogi search report of which she was aware, did not raise a patentability problem with respect to Sandoz, and a full copy of the Sandoz reference was not sent to her." These internal search reports do not show the chemical structures of the Sandoz reference. The district court found that the evidence showed that after Ms. Kitamura's departure, Shionogi was not alerted to the need for further attention to the Sandoz reference because of "chaos, confusion, and inexperience," "lack of legal training within the Shionogi Patent Department, the changing and limited personnel within that department, . . . the ongoing confusion level," and "unintentional miscommunications" between Shionogi's patent personnel. These findings have not been shown to be clearly erroneous. And the Defendants' charge that Shionogi deliberately obtained claims in the '440 patent that it knew to be invalid is not plausible. The district court found that "the Court is ultimately not convinced that the claims of the '440 patent that overlapped the Sandoz reference were the result of some planned strategy or sinister motivation as opposed to mere mistake or oversight by overworked individuals with limited training and expertise." . . .

"The law does not require that no competent attorney or alert inventor could have avoided the error sought to be corrected by reissue." The Shionogi error in failing to file an IDS was agreed to be an error, and was rectified promptly upon its discovery. Our colleague in dissent does not complain about the speed of the moves to correct the error, but would hold that the error should have been detected sooner, and that this failure of detection is fatal to the reissue patent. However, all of the cited cases relate to the absence of diligence in correcting the error after it was detected. In contrast, the reissue application here was filed promptly upon discovery of the error. . . . In sum, the district court correctly found that reissue was available, and that the scope of the reissue was in accordance with law.

If you have questions about the material presented above, please contact Dr. Lawrence M. Sung ( or 202.861.1537) or any member of our Intellectual Property Team.

See information regarding BakerHostetler's Patent Litigation and IP Prosecution and Portfolio Management practices.

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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